Biphenyl-derivatives as p38-kinase inhibitors

ABSTRACT

Compounds of formula (I): 
                         
or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/EP02/11571 filed Oct. 16, 2002, which claims priority from GB0124934.1 filed Oct. 17, 2001.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of certain diseases and conditions.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

R¹ is a phenyl group which may be optionally substituted;

R² is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl;

R³ is the group —NH—CO—R⁴;

R⁴ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, trifluoromethyl, —(CH₂)_(r)phenyl optionallysubstituted by R⁵ and/or R⁶, —(CH₂)_(r)heteroaryl optionally substitutedby R⁵ and/or R⁶, —(CH₂)_(r)heterocyclyl optionally substituted by R⁵and/or R⁶ and —(CH₂)_(r)fused bicyclyl optionally substituted by R⁵and/or R⁶;

R⁵ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl,—CONR⁷R⁸, —NHCOR⁸, —SO₂NHR⁷, —NHSO₂R⁸, halogen, —(CH₂)_(s)NR⁹R¹⁰, oxy,trifluoromethyl, phenyl optionally substituted by one or more R⁸ groupsand heteroaryl wherein the heteroaryl may be optionally substituted byone or more R⁶ groups;

R⁶ is selected from C₁₋₈alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and—NR⁹R¹⁰;

or R⁵ and R⁶, together with the carbon atoms to which they are bound,form a five- or six-membered saturated or unsaturated ring to give afused bicyclic ring system, wherein the ring that is formed by R⁵ and R⁶may optionally contain one or two heteroatoms selected from oxygen,nitrogen and sulfur;

R⁷ is selected from hydrogen, C₁₋₆alkyl and phenyl wherein the phenylgroup may be optionally substituted by one or more R⁶ groups;

R⁸ is selected from hydrogen and C₁₋₆alkyl;

or R⁷ and R⁸, together with the nitrogen atom to which they are bound,form a five- to six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R^(x), whereinthe ring may be substituted by up to two C₁₋₆alkyl groups;

R^(x) is selected from hydrogen and methyl;

R⁹ is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloaklyoptionally substituted by C₁₋₆alkyl;

R¹⁰ is selected from hydrogen and C₁₋₆alkyl;

or R⁹ and R¹⁰, together with the nitrogen atom to which they are bound,form a three- to seven-membered heterocyclic ring optionally containingone additional heteroatom selected from oxygen, sulfur and N—R^(x),wherein the ring may contain up to one double bond and the ring may besubstituted by one or more R¹¹ groups;

R¹¹ is selected from C₁₋₆alkyl, oxy, —CH₂OC₁₋₆alkyl, trichloromethyl and—N(C₁₋₆alkyl)₂;

U is selected from methyl and halogen;

W is selected from methyl and chlorine;

X and Y are each selected independently from hydrogen, methyl andhalogen;

m is selected from 0, 1, 2, 3 and 4, and may be optionally substitutedwith up to two groups selected independently from C₁₋₆alkyl;

n is selected from 0, 1 and 2;

q is selected from 0, 1 and 2;

r is selected from 0 and 1;

s is selected from 0, 1, 2 and 3;

or a pharmaceutically acceptable salt or solvate thereof.

According to a further embodiment of the invention there is provided acompound of formula (IA):

wherein

R¹, R², R³ and m are as defined above, or a pharmaceutically acceptablesalt or solvate thereof.

In a preferred embodiment, the molecular weight of a compound of formula(I) does not exceed 1000, more preferably 800, even more preferably 600.

The group R¹ may be optionally substituted by up to three substituents,more preferably one or two substituents, selected independently from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, trifluoromethyl,benzyloxy, hydroxy, cyano, hydroxyC₁₋₆alkyl,—(CH₂)_(p)CO(CH₂)_(t)NR¹⁰R¹¹, —(CH₂)_(p)CO₂R¹⁰, —(CH₂)_(p)NR¹⁰COR¹¹,—(CH₂)_(p)OCOR¹⁰, —(CH₂)_(p)OCONR¹⁰R¹¹, —(CH₂)_(p)NR¹⁰COOR¹¹,—(CH₂)_(p)COR¹⁰, —(CH₂)_(p)SO₂NR¹⁰R¹¹, —(CH₂)_(p)NR¹⁰SO₂R¹¹, —SO₂R¹⁰,—(CH₂)_(p)NR¹⁰R¹¹, —O(CH₂)_(p)NR¹⁰R¹¹, —(CH₂)_(p)NR¹⁰CO(CH₂)_(t)NR¹⁰R¹¹,—(CH₂)_(p)CONR¹⁰SO₂R¹¹, —(CH₂)_(p)SO₂NR¹⁰COR¹¹ and phenyloxy optionallysubstituted by a group A; or R¹ may be optionally substituted by twoadjacent substituents which, together with the carbon atoms to whichthey are bound, form a five- or six-membered saturated or unsaturatedring to give a fused bicyclic ring system. The ring that is fused to thephenyl ring may optionally contain one or two heteroatoms selected fromoxygen, nitrogen and sulfur. The group R¹ may also be optionallysubstituted by three, more preferably one or two, C₃₋₇cycloalkyl groups.

R¹⁰ and R¹¹ are independently selected from hydrogen, C₁₋₆alkyl,trihalomethyl, benzyl, —(CH₂)_(v)OH, —(CH₂)_(v)NR¹²R¹³ and phenyloptionally substituted by up to three groups selected from C₁₋₆alkyl andC₁₋₆alkoxy.

R¹² and R¹³ are independently selected from hydrogen and C₁₋₄alkyl.

A is selected from halogen, —SO₂NH₂, —SO₂-(4-methyl)piperazinyl,—NR¹⁰COC₁₋₆alkyl and —NR¹⁰SO₂C₁₋₆alkyl.

p is selected from 0, 1, 2 and 3.

t is selected from 0, 1, 2 and 3.

v is selected from 2 and 3.

The optional substituents on the group R¹, including when the phenylring is part of a fused bicyclic system, may be located on any positionon the phenyl ring. In a more preferred embodiment, when there is onesubstituent on the group R¹, that substituent is located on the meta- orpara-position relative to the amide linkage. When there are two optionalsubstituents on the group R¹, these substituents preferably occupy themeta- and para-positions relative to the amide linkage.

Preferred subtituents for the group R¹ are halogen, C₁₋₄alkyl,trifluromethyl, C₁₋₄alkoxy, phenyloxy optionally substituted by thegroup A, benzyloxy, hydroxy, cynao, —CH₂CH₂OH, —(CH₂)_(p)-NHCH₃,—(CH₂)_(p)-N(CH₃)₂, —(CH₂)_(p)CONR¹⁰R¹¹, —(CH₂)_(p)CO₂R¹⁰,—(CH₂)_(p)NR¹⁰COR¹¹, —(CH₂)_(p)OCOR¹⁰, —(CH₂)_(p)OCONR¹⁰R¹¹,—(CH₂)_(p)NR¹⁰COOR¹¹, —(CH₂)_(p)COR¹⁰, —(CH₂)_(p)SO₂NR¹⁰R¹¹,—(CH₂)_(p)NR¹⁰SO₂R¹¹, —SO₂R¹⁰, —(CH₂)_(p)NR¹⁰R¹¹,—(CH₂)_(p)NR¹⁰CONR¹⁰R¹¹ and —(CH₂)_(p)CONR¹⁰SO₂R¹¹. In a particularlypreferred embodiment, substituents for the group R¹ are selected fromC₁₋₄alkoxy, in particular methoxy; hydroxy; —(CH₂)_(p)NR¹⁰SO₂R¹¹, inparticular —NHSO₂CH₃ or —CH₂NHSO₂CH₃; and —(CH₂)_(p)NR¹⁰R¹¹, inparticular —CH₂N(CH₃)₂. In a preferred embodiment, R² is selected fromhydrogen, C₁₋₄alkyl and —CH₂-cyclopropyl, more preferably hydrogen.

In a preferred embodiment, R⁴ is selected from —(CH₂)_(r)phenyloptionally substituted by R⁵ and/or R⁶ and —(CH₂)_(r)heteroaryloptionally substituted by R⁵ and/or R⁶. In a particularly preferredembodiment, R⁴ is —(CH₂)_(r)heteroaryl optionally substituted by R⁵and/or R⁶, especially furyl, thienyl, isoxazolyl or pyridyl optionallysubstituted by —(CH₂)_(s)NR⁹R¹⁰.

In a preferred embodiment, R⁵ is selected from C₁₋₄alkyl, halogen,—NR⁹R¹⁰, C₃₋₆cycloalkyl, phenyl optionally substituted by one or more R⁶groups and heteroaryl optionally substituted by one or more R⁶ groups.

In a preferred embodiment, R⁶ is selected from C₁₋₂alkyl and halogen. Ina further preferred embodiment, R⁶ is —NR⁹R¹⁰.

In a preferred embodiment, R⁷ is selected from hydrogen and C₁₋₄alkyl.

In a preferred embodiment, R⁸ is selected from hydrogen and C₁₋₄alkyl.

In a preferred embodiment, R⁹ is selected from hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl and —CH₂C₃₋₆cycloalkyl.

In a preferred embodiment, R¹⁰ is selected from hydrogen and C₁₋₄alkyl.

In a preferred embodiment, R⁹ and R¹⁰, together with the nitrogen atomto which they are bound, form a five to six membered heterocyclic ringoptionally containing up to one additional heteroatom selected fromoxygen, sulfur and N—R^(x), wherein R^(x) is methyl, and the ring may besubstituted by one or more R¹¹ groups. In a further preferredembodiment, R⁹ and R¹⁰, together with the nitrogen atom to which theyare bound, form a pyrrolidinyl group.

In a preferred embodiment, R¹¹ is selected from methyl and oxy.

In a preferred embodiment, W is methyl.

In a preferred embodiment, X and Y are each selected independently fromhydrogen, chlorine and fluorine. In a further preferred embodiment, X isfluorine.

In a preferred embodiment, m is selected from 0, 1 and 2.

In a preferred embodiment, n is selected from 0 and 1. In particular, nis 0.

In a preferred embodiment, p, s and t are independently selected from 0,1 and 2.

In a preferred embodiment, q and r are independently 0.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts andsolvates. Specific examples which may be mentioned include:

-   N-(4′-{[(3-Methoxybenxyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide;    and-   N-{4′-[(4-Methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide.

Further specific examples which may be mentioned include:

-   N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;-   N-(4′-{[(4-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;-   N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carbonamide;-   N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;-   N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide;-   N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)-carbonyl]-1,1′-biphenyl-3-yl}isoxazole-5-carboxamide;-   N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)-amino]-carbonyl}-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide;-   N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;-   N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;-   N-{4′-[({3-[(Dimethylamino)methyl]benzyl}amino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;-   N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;-   N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;-   N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;-   N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)amino]-carbonyl}-1,1′-biphenyl-3-yl)-3-furamide;    and-   N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}-3-furamide.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl or isopropyl. The said alkyl groupmay be optionally substituted with one or more fluorine atoms, forexample, trifluoromethyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.A C₁₋₄alkoxy group is preferred, for example methoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms. Forexample, C₃₋₇cycloalkyl means a non-aromatic ring containing at leastthree, and at most seven, ring carbon atoms. Examples of “cycloalkyl” asused herein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₅ cycloalkyl group ispreferred, for example cyclopropyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to amonocyclic five- to seven-membered unsaturated hydrocarboned ringcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Preferably, the heteroaryl ring has five or sixring atoms. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, andtriazinyl. A particularly preferred heteroaryl ring is pyridyl. The saidring may be optionally substituted by one or more substituentsindependently selected from C₁₋₆alkyl and oxy.

As used herein, the terms “heterocyclic ring” and “heterocyclyl” referto a monocyclic three- to seven-membered saturated or non-aromatic,unsaturated hydrocarbon ring containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Preferably, theheterocyclyl ring has five or six ring atoms. Examples of heterocyclylgroups include, but are not limited to, aziridinyl, pyrrolinyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidyl, piperazinyl, morpholino, and thiomorpholino. The said ringmay be optionally substituted by one or more substituents independentlyselected from C₁₋₆alkyl and oxy.

As used herein, the terms “fused bicyclic ring system” and “fusedbicyclyl” refer to a ring system comprising two five- to seven-memberedsaturated or unsaturated hydrocarbon rings, the ring system optionallycontaining one or more heteroatoms independently selected from oxygen,nitrogen and sulfur. Preferably, each ring has five or six ring atoms.Examples of suitable fused bicyclic rings include, but are not limitedto, naphthyl, indolyl, indolinyl, benzothienyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzodioxzanyl, indanyl and tetrahydronaphthyl. Eachring may be optionally substituted with one or more substituentsindependently selected from halogen, C₁₋₆alkyl, oxy, —(CH₂)_(p)NR¹⁰R¹¹,—CO(CH₂)_(p)NR¹⁰R¹¹, and imidazolyl. Particularly preferred substituentsare chlorine, imidazolyl and —CH₂—N(CH₃)₂.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol and aceticacid. Most preferably the solvent used is water.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoinclude within the scope of the present invention.

Salts of the compounds of the present invention are also encompassedwithin the scope of the invention and may, for example, comprise acidaddition salts resulting from reaction of an acid with a nitrogen atompresent in a compound of formula (I).

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention.Representative salts include the following salts: Acetate,Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate,Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

For example, a general method (A) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 1 below.

(i) Di-t-butyldicarbonate, Et₃N, DCM

(ii) (4-Methoxycarbonylphenyl)boronic acid, (Ph₃P)₄Pd, CsCO₃, DME

(iii) LiOH, THF, H₂O

(iv) R¹(CH₂)_(m)N R²H, HATU, DIPEA, THF

(v) TFA, DCM

(vi) R⁴COOH, HATU, DIPEA, DMF

For example, a general method (B) for preparing the compound of Formula(I) comprises the reactions set out in Scheme 2 below.

(i) (4-Methoxycarbonylphenyl)boronic acid, (Ph₃P)₄Pd, CsCO₃, DME

(ii) R⁴COOH, HATU, DIPEA, DMF

(iii) LiOH, THF, H₂O

(iv) R¹(CH₂)_(m)N R²H, HATU, DIPEA, THF

For example, a general method (C) for preparing the compounds of Formula(I) wherein R⁴ is

comprises the reactions set out in Scheme 3 below.

(i) Et₃N, DCM

(ii) LiOH, THF, H₂O

(iii) R′R″NH

(iv) R¹(CH₂)_(m)N R²H, HATU, DIPEA, THF

For example, a general method (D) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 4 below:

(i) (4-Methoxycarbonylphenyl)boronic acid, (Ph₃P)₄Pd, CsCO₃, DME

(ii) LiOH, THF, H₂O

(iii) R¹(CH₂)_(m)N R²H, HATU, DIPEA, THF

(iv) R⁴COCl, ET₃N, DCM

Thus, according to the invention there is provided a process forpreparing a compound of formula (I) which comprises:

-   (a) reacting a compound of formula (IX)

wherein

R¹, R², U, W, X, Y, m and n are as defined above, with a compound offormula (X)R⁴CO₂H  (X)wherein

R⁴ is as defined above, under amide forming conditions (if desired, theacid compound (X) may be converted to an activated form of the acid, forexample the acid chloride, and then the activated acid thus formedreacted with the amine compound (IX)); or

-   (b) reacting a compound of formula (XI)

wherein

R³, U, W, X, Y and n are as defined above, with a compound of formula(XII)R¹(CH₂)_(m)NR₂H  (XII)wherein

R¹, R² and m are as defined above, under amide forming conditions.

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid, in for example THF, with an amine inthe presence of, for example, HATU and DIPEA.

Whilst it is possible for the compounds, salts or solvates of thepresent invention to be administered as the new chemical, the compoundsof formula (I) and their pharmaceutically acceptable salts and solvatesare conveniently administered in the form of pharmaceuticalcompositions. Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof in admixture withone or more pharmaceutically acceptable carriers, diluents orexcipients.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvants may be formulated for administration in any suitablemanner. They may, for example, be formulated for topical administrationor administration by inhalation or, more preferably, for oral,transdermal or parenteral administration. The pharmaceutical compositionmay be in a form such that it can effect controlled release of thecompounds of formula (I) and their pharmaceutically acceptable salts andsolvates. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), pills, powders, granules, elixirs,tinctures, emulsions, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar—agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acadia mucilage or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidycholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon, caproactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmicotic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative. Alternatively for parenteraladministration the active ingredient may be in powder form forreconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluorethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalue to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in human is accomplished by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the age, weightand response of the particular individual. The effectiveness of aselected actual dose can readily be determined, for example, bymeasuring clinical symptoms or standard anti-inflammatory indicia afteradministration of the selected dose. The above dosages are exemplary ofthe average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention. For conditions or disease states as are treated bythe present invention, maintaining consistent daily levels in a subjectover an extended period of time, e.g., in a maintenance regime, can beparticularly beneficial.

In another aspect, the present invention provides a compound of formula(I) or a salt or solvate thereof, for use in therapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrated according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselected for one or more of the isoforms of p38, for example p38α, p38β,p38γ and/or p38δ. In one embodiment, the compounds of the inventionselectively inhibit the p38α isoform. In another embodiment, thecompounds of the invention selectively inhibit the p38β isoform. In afurther embodiment, the compounds of the invention selectively inhibitthe p38α and p38β isoforms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/71535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active in an inappropriatelocation, p38 kinase can be constitutively expressed, or p38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a method for the treatmentof a condition or disease state mediated by p38 kinase activity, ormediated by cytokines produced by the activity of p38 kinase, in asubject which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof. The compound may be administered asa single or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diasteroisomer or a mixture ofdiastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiasteroisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments.

The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to aquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesis, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvant thereof.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state mediated by p38 kinase activity or medicated by cytokinesproduced by p38 kinase activity.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, osteoarthritis,asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis,adult respiratory distress syndrome, chronic pulmonary inflammation,chronic obstructive pulmonary disease, chronic heart failure, silicosis,endotoxemia, toxic shock syndrome, inflammatory bowel disease,tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritablebowel syndrome, muscle degeneration, bone resorption diseases,osteoporosis, diabetes, reperfusion injury, graft vs. host reaction,allograft rejections, sepsia, systemic cachexia, cachexia secondary toinfection or malignancy, cachexia secondary to aquired immune deficiencysyndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis,Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, and cancer including breast cancer, colon cancer, lungcancer or prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, asthma, psoriasis,chronic pulmonary inflammation, chronic obstructive pulmonary disease,chronic heart failure, systemic cachexia, glomerulonephritis, Crohn'sdisease, neurodegenerative disease, Alzheimer's disease, Parkinson'sdisease, epilepsy, and cancer including breast cancer, colon cancer,lung cancer and prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, asthma, psoriasis,chronic pulmonary inflammation, chronic obstructive pulmonary disease,chronic heart failure, systemic cachexia, glomerulonephritis, Crohn'sdisease and cancer including breast cancer, colon cancer, lung cancerand prostatic cancer.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of a condition ordisease state selected from rheumatoid arthritis, neurodegenerativedisease, Alzheimer's disease, Parkinson's disease and epilepsy.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the preparation of a medicament for the treatment of any type ofpain including chronic pain, rapid onset of analgesis, neuromuscularpain, headache, cancer pain, acute and chronic inflammatory painassociated with osteoarthritis and rheumatoid arthritis, post operativeinflammatory pain, neuropathic pain, diabetic neuropathy, trigeminalneuralgia, post-hepatic neuralgia, inflammatory neuropathies andmigraine pain.

The compounds of formula (I) and their salts, solvates andphysiologically functional salts and solvates may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in rheumatoid arthritistherapy, combination with other chemotherapeutic or antibody agents inenvisaged. Combination therapies according to the present invention thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof and at least oneother pharmaceutically active agent. The compound(s) of formula (I) orpharmaceutically acceptable salt(s) or solvate(s) thereof and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately, this may occur separatelyor sequentially in any order. The amounts of the compound(s) of formula(I) or pharmaceutically acceptable salt(s) or solvant(s) thereof and theother pharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Examples of other pharmaceutically active agentswhich may be employed in combination with compounds of formula (I) andtheir salts and solvates for rheumatoid arthritis therapy include:immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone;anti-TNFα agents such as etanercept, infliximab, diacerein; tyrosinekinase inhibitors such as leflunomide; kalikrein antagonists such assubreum; interleukin 11 agonists such as oprelvekin; interferon beta 1agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amytoid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

EXAMPLES

The following examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 um ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm.

Example 1N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide

a)2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylicacid

(40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA(52 μl), and 3-methoxybenzlamine (16.5 mg, 0.12 mmol) were mixed in DMF(1 ml) and stirred at room temperature for 18 h. The solvent wasevaporated under vacuum and the residue partitioned between DCM (5 ml)and aqueous sodium carbonate (1M, 5 ml). The organic phase was appliedto a silica gel flash column and eluted with toluene/methanol (95:5),which after evaporation of the solvents under vacuum gaveN-(4′-{[(3-methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide(21 mg, 40%).

NMR; δH [²H₆]—DMSO 10.28, (1H, s), 9.09, (1H, t), 8.19, (1H, d), 7.97,(2H, d), 7.71, (1H, d), 7.66, (1H, s), 7.46, (2H, d), 7.30, (1H, d),7.24, (1H, t), 6.96–6.80, (5H, m), 4.47, (2H, d), 3.73, (3H, s), 3.43,(4H, m), 2.21, (3H, s), 1.95, (4H, m). LCMS: retention time 2.95 min,MH⁺521.

b)2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylicacid

5′-[(2-Chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylicacid (600 mg, 1.64 mmol) and pyrrolidine (0.6 ml) were heated in asealed tube at 90° C. for 5 h. The excess pyrrolidine was evaporatedunder vacuum and the residue purified by flash chromatography (silica)eluting with DCM/ethanol/ammonia (20:8:1). The solvents were evaportatedunder vacuum to give2′-methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylicacid (546 mg, 83%).

LCMS: retention time 2.74 min, MH⁺402.

c)5′-[(2-Chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylicacid

Methyl5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate(1.63 g, 4.28 mmol) and lithium hydroxide monohydrate (376 mg, 9.0 mmol)were mixed in water (5 ml) and THF (10 ml) and stirred at roomtemperature for 90 h. The pH was adjusted to pH3 by addition ofhydrochloric acid (2N) and the mixture extracted with ethyl acetate(3×50 ml). The combined extracts were washed with water (75 ml), brine(75 ml), dried (magnesium sulphate) and concentrated under vacuum. Theresidue was purified by flash column chromatography on silica elutingwith DCM/ethanol/ammonia (30:8:1 then 20:8:1). The solvents wereevaporated under vacuum to give5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylicacid (1.15 g, 73%).

LCMS: retention time 3.53 min, MH⁺367.

d) Methyl5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate

2-Chloropyridine-4-carbonyl chloride (1.58 g, 9.0 mmol) in DCM (10 ml)was added dropwise to a solution of methyl5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.81 g, 7.5 mmol) andtriethylamine (3.13 ml, 22.5 mmol) in DCM (10 ml) at 0° C. The reactionwas stirred at room temperature for 20 h, the solvent evaporated undervacuum and the residue partitioned between ethyl acetate (50 ml) andsaturated aqueous sodium bicarbonate (50 ml). The aqueous was extractedwith ethyl acetate (50 ml) and the combined organic phases washed withbrine (50 ml), dried (magnesium sulphate) and the solvent evaporatedunder vacuum. The residue was purified by flash column chromatography onsilica eluting with DCM/ethanol/ammonia (300:8:1). The solvents wereevaporated under vacuum to give methyl5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate(1.73 g, 61%).

LCMS: retention time 3.69 min, MH⁺381.

e) Methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate

3-Bromo-4-methylaniline (744 mg, 4.0 mmol),(4-methoxycarbonylphenyl)boronic acid (864 mg, 4.8 mmol),tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol) and caesiumcarbonate (2.4 g, 7.37 mmol) were mixed in DME (30 ml) and heated at 90°C. for 20 h. The reaction was absorbed onto silica applied to a silicaSPE (10 g) and eluted with ethyl acetate/cyclohexane (0–100% ethylacetate). The solvent was evaporated from the product fractions undervacuum to give methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate(500 mg, 43%).

NMR; δH CDCl₃ 8.07, (2H, d), 7.38, (2H, d), 7.07, (1H, d), 6.67, (1H,dd), 6.60, (1H, d), 3.94, (3H, s), 2.14, (3H, s).

Example 2N-{4′-[(4-Methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide

2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylicacid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol),DIPEA (52 μl), and 4-methoxyaniline (15 mg, 0.12 mmol) were mixed in DMF(1 ml) and stirred at room temperature for 18 h. The solvent wasevaporated under vacuum and the residue partitioned between DCM (5 ml)and aqueous sodium carbonate (1M, 5 ml). The organic phase was appliedto a silica gel flash column and eluted with DCM/ethanol/ammonia(400:8:1 then 300:8:1), which, after evaporation of the solvents undervacuum, gaveN-{4′[(4-methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide(16 mg, 30%).

NMR; δH [²H₆]—DMSO 10.29, (1H, s), 10.19, (1H, s), 8.19, (1H, d), 8.02,(2H, d), 7.73–7.68, (4H, m), 7.50, (2H, d), 7.31, (1H, d), 6.97–6.92,(3H, m), 6.86, (1H, s), 3.74, (3H, s), 3.43, (4H, m), 2.23, (3H, s),1.95, (4H, m). LCMS: retention time 3.02 min, MH⁺507.

Example 3N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamideExample 4N-(4′-{[(4-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamideExample 5N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamideExample 6N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide

General Method A

{3′[(3-Thiphenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (Intermediate 1, 50 mg, 0.148 mmol), HOBT (20 mg, 0.148 mmol),DIPEA (30.7 μl, 0.178 mmol), EDC (34.1 mg, 0.178 mmol) and the amine(0.148 mmol) were stirred in DMF (1 ml) at room temperature for 2 hours.The reaction was diluted with ethyl acetate (50 ml), washed withhydrochloric acid (0.5M, 2×50 ml), aqueous sodium hydrogen carbonate(2×50 ml) and dried (magnesium sulphate). The solution was reduced todryness under vacuum to give the desired product.

Retention time Compound Amine MH⁺ (minutes) Example 32-hydroxybenzylamine 443 3.54 Example 4 4-hydroxybenzylamine 443 3.31Example 5 3-hydroxybenzylamine 443 3.35 Example 63,5-dihydroxybenzylamine 459 3.20

(a){3′-[(3-Thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (Intermediate 1)

A solution of lithium hydroxide monoxide monohydrate (541 mg, 12.9 mmol)in water (8 ml) was added to a solution of methyl{3′-](3-thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate(Intermediate 2, 1.37 g, 4.3 mmol) in THF (10 ml). The reaction wasrefluxed for 4 hours. Solvent was evaporated in vacuo, hydrochloric acid(0.5M, 50 ml) was added and the product was extracted into ethyl acetate(2×50 ml). The solvent was evaporate in vacuo to afford{3′[(3-thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (1.68 g, 98%).

NMR: δH [²H₆]—DMSO 13.10, (1H, bs), 8.33, (1H, dd), 8.03, (2H, d), 7.72,(1H, dd), 7.68–7.60, (3H, m) 7.50, (2H, d), 7.30, (1H, d), 2.20, (3H,s). LCMS: MH⁺ 338, retention time 3.47 minutes.

(b) Methyl{3′-[(3-thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate(Intermediate 2)

Methyl (3′-amino-6′-methyl-1,1′-biphen-4-yl)carboxylate (1.45 g, 6.0mmol), thiophene-3-carboxylic acid (0.846 g, 6.6 mmol), HOBT (0.973 g,7.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.38 g, 7.2 mmol) were dissolved in DMF (10 ml). DIPEA(1.26 ml, 7.2 mmol) was added to the stirred solution, which was thenstirred for 16 hours at 20° C. The solvent was removed in vacuo and theresidue dissolved in ethyl acetate. The ethyl acetate solution waswashed sequentially with aqueous sodium hydrogen carbonate (80 ml) andhydrochloric acid (0.5M, 80 ml), then dried (magnesium sulphate). Thesolvent was removed in vacuo and the residue was purified by silicabiotage chromatography eluting with 4:1 cyclohexane:ethyl acetate. Togive methyl{3′-[(3-thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate(1.78 g, 84%).

NMR: δH [²H₆]—DMSO 10.1, (1H, s), 8.33, (1H, m), 8.05, (2H, d), 7.72,(1H, dd), 7.70–7.60, (3H, m) 7.52,(2H, d), 7.30, (1H, d), 3.89, (3H, s),2.20, (3H, s). LCMS: MH⁺ 352, retention time 3.64 minutes.

Example 7N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide

{3′-[(5-Isoxazolylycarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (Intermediate 3, 30 mg), 3-methoxybenzylamine (12.8 mg), HATU (35mg), HOBT (13 mg) and DIPEA (48 μl) in DMF (1 ml) were stirred for 18hours at room temperature. The reaction was diluted with ethyl acetate(50 ml), washed with hydrochloric acid (0.5M, 2×25 ml), aqueous sodiumhydrogen carbonate (2×25 ml), dried (magnesium sulphate) and the solventevaporated in vacuo. The residue was purified by mass-directed autoprepto giveN-(4′-{[(3-methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide.

NMR; δH [²H₆]—DMSO 10.76, (1H, s), 9.11, (1H, t), 8.82, (1H, d), 7.98,(2H, d), 7.72, (1H, dd), 7.68, (1H, d), 7.47, (2H, d), 7.33, (1H, d),7.28–7.23, (2H, m), 6.92, (2H, m), 6.82, (1H, m), 4.49, (2H, d), 3.75,(3H, s), 2.23, (3H, s). LCMS: MH⁺ 442, retention time, 3.27 minutes.

(a){3′-[(5-Isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (Intermediate 3)

Methyl{3′-[(5-isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate(Intermediate 4, 2.84 g), sulphuric acid (1M, 50 ml) and ethanol (100ml) were heated at 75° C. for 2 hours. The reaction was concentratedunder vacuum and the resulting precipitate filtered off and washed withwater. The resulting solid was purified on a flash silica column elutingwith an ethyl acetate/cyclohexane gradient (33–66% ethyl acetate.Evaporation of the solvent under vacuum gave[3′-(5-isoxazolylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid.

LCMS: MNH₄ ⁺ 340, retention time, 3.11 minutes.

(b) Methyl{3′-[(5-Isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate(Intermediate 4)

Methyl (3′-amino-6′-methyl-1,1′-biphen-4-yl)carboxylate (2 g), HATU(3.16 g), DIPEA (4.32 ml), 5-isoxazolecarboxylic acid (0.95 g) in DMF(30 ml) and ethyl acetate (50 ml) were stirred at room temperature for 2hours. The reaction was diluted with ethyl acetate (500 ml), washed withhydrochloric acid (0.5M, 2×200 ml), aqueous sodium hydrogen carbonate(2×200 ml) and dried (magnesium sulphate). The solvent was evaporated invacuo to give methyl{3′-[(5-isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylate.

LCMS: [M-H]⁻ 335, retention time 3.17 minutes.

Example 8N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)-carbonyl]-1,1′-biphenyl-3-yl}isoxazole-5-carboxamide

{3′-[(5-Isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (30 mg), N-(4-aminophenyl)methane sulphonamide (17.4 mg), HATU (35mg), HOBT (13 mg) and DIPEA (48 μl) in DMF (1 ml) were stirred for 18hours at room temperature. The reaction was diluted with ethyl acetate(50 ml), washed with hydrochloric acid (0.5M, 2×25 ml), aqueous sodiumhydrogen carbonate (2×25 ml), dried (magnesium sulphate) and the solventevaporated in vacuo. The residue was purified by mass-directed autoprepto giveN-{6-methyl-4′[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}isoxazole-5-carboxamide.

NMR; δH [²H₆]—DMSO 10.76, (1H, s), 10.32, (1H, s), 9.60, (1H, s), 8.81,(1H, d), 8.03, (2H, d), 7.76–7.69, (4H, m), 7.52, (2H, d), 7.33, (1H,d), 7.24, (1H, d), 7.20, (2H, d), 2.95, (3H, s), 2.23, (3H, s). LCMS:MH⁺ 491, retention time, 3.12 minutes.

Example 9N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)-amino]carbonyl}-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide

{3′-[(5-Isoxazolylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (30 mg), N-(4-aminobenzyl)methane sulphonamide (18.6 mg), HATU (35mg), HOBT (13 mg) and DIPEA (48 μl) in DMF (1 ml) were stirred for 18hours at room temperature. The reaction was diluted with ethyl acetate(50 ml), washed with hydrochloric acid (0.5M, 2×25 ml), aqueous sodiumhydrogen carbonate (2×25 ml), dried (magnesium sulphate) and the solventevaporated in vacuo. The residue was purified by mass-directed autoprepto giveN-(6-methyl-4′-{](4-{](methylsulfonyl)amino]methyl}phenyl)amino]carbonyl}-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide.

NMR; δH [²H₆]—DMSO 10.76, (1H, s), 10.33, (1H, s), 8.81, (1H, d), 8.03,(2H, d), 7.77, (2H, d), 7.72–7.70, (2H, m), 7.52, (3H, m), 7.34, (3H,m), 7.24, (1H, d), 4.13, (2H, d), 2.84, (3H, s), 2.24, (3H, s). LCMS:MNH₄ ⁺ 522, retention time, 3.10 minutes.

Example 10N-4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamideExample 11N-{6-Methyl-4′-[({4-](methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}thiophene-3-carboxamide

General Method B

{3′-[(3-Thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (40 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (27 mg, 0.14 mmol), HOBT (19 mg, 0.14 mmol) and theappropriate amine (0.13 mmol) were dissolved in DMF (5 ml). DIPEA (25μl, 0.14 mmol) was added to the solution which was then stirred from 16hours at 20° C. The solvent was removed in vacuo and the residue wasredissolved in ethyl acetate and washed with water. The ethyl acetatelayer was separated, dried (magnesium), concentrated in vacuo andpurified by mass-directed HPLC.

Retention time Compound Amine MH⁺ (minutes) Example 103-methoxybenzylamine 457 3.54 Example 11 N-(4-aminophenyl)methane 5063.28 sulphonamide

Example 12N-(4′-[({3-[(Dimethylamino)methyl]benzyl}amino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}thiophene-3-carboxamide

{3′-[(3-Thiophenylcarbonyl)amino]-6′-methyl-1,1′-biphen-4-yl}carboxylicacid (40 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (27 mg, 0.14 mmol), HOBT (19 mg, 0.14 mmol) and the3-(N,N-dimethylaminomethyl)benzylamine (0.13 mmol) were dissoved in DMF(5 ml). DIPEA (25 μl, 0.14 mmol) was added to the solution which wasthen stirred for 16 hours at 20° C. Solvent was removed in vacuo and theresidue was redissolved in ethyl acetate and washed with water, dried(magnesium sulphate) and concentrated in vacuo. The residue was purifiedby mass-directed HPLC to giveN-[4′-[({3-[(dimethylamino)methyl]benzyl}amino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}thiophene-3-carboxamide.

LC/MS: MH⁺ 484, retention time 2.61 minutes.

Example 13N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamideExample 14N-(4′{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furmamideExample 15N-(4′{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide

General Method C

]3′-(3-Furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid(Intermediate 5, 50 mg, 0.148 mmol), HOBT (20 mg, 0.148 mmol), DIPEA(30.7 μl, 0.178 mmol), EDC (34.1 mg, 0.178 mmol) and the amine (0.148mmol) were stirred in DMF (1 ml) at room temperature for 2 hours. Thereaction was diluted with ethyl acetate (50 ml), washed withhydrochloric acid (0.5M, 2×50 ml), aqueous sodium hydrogen carbonate(2×50 ml) and dried (magnesium sulphate). The solution was reduced todryness under vacuum to give the desired product.

Retention time Compound Amine MH⁺ (minutes) Example 133,5-dihydroxybenzylamine 443 3.09 Example 14 2-hydroxybenzylamine 4273.43 Example 15 3-hydroxybenzylamine 427 3.23

(a) [3′-(3-Furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid(Intermediate 5)

Methyl [3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylate(Intermediate 6, 980 mg, 2.9 mmol) and lithium hydroxide monohydrate(256 mg, 6.1 mmol) in THF (12 ml) and water (6 ml) were heated at 75° C.for 18 h. The THF was evaporated under vacuum and the aqueous adjustedto pH3 with hydrochloric acid (1M). The precipitate which formed wasfiltered off, washed with ether and dried under vacuum to give[3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid (720 mg,77%).

LCMS: retention time 3.33 min, MH⁺322.

(b) Methyl [3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylate(Intermediate 6)

3-Furoic acid (557 mg, 4.97 mmol), HATU (1.89 g, 4.97 mmol), HBTU (560mg, 4.14 mmol), methyl (3′-amino-6′-methyl-1,1′-biphen-4-yl)carboxylate(1.0 g, 4.14 mmol) and DIPEA (2.17 ml, 12.43 mmol) were mixed in DMF (5ml) and reaction stirred at room temperature for 18 h. The DMF wasevaporated under vacuum, the residue partitioned between DCM (50 ml) andaqueous sodium carbonate (1M, 50 ml) and the aqueous extracted with DCM(2×30 ml). The combined organics were washed with brine (75 ml), dried(magnesium sulphate) and concentrated under vacuum. The residue waspurified on a silica flash column eluting with DCM/ethanol/ammonia(500:8:1), which after evaporation of the solvents under vacuum gavemethyl [3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylate (800mg, 58%).

LCMS: retention time 3.41 min, MH⁺336.

Example 16N-(6-Methyl-4′{[(4-{[(methylsulfonyl)amino]methyl}phenyl)amino]-carbonyl}-1,1′-biphenyl-3-yl)-3-furamide

To a solution of[3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid (75 mg),HATU (89 mg) and HOBT (32 mg) in DMF (2.25 ml) was added DIPEA (0.122ml) and N-[(4-aminophenyl)methyl]methane sulphonamide (47 mg) and themixture stirred for 18 hours at room temperature. The reaction waspartitioned between ethyl acetate and hydrochloric acid (0.5M, 20 ml),the organic phase washed with hydrochloric acid (0.5M, 20 ml), saturatedsodium hydrogen carbonate solution (2×20 ml) and water (2×20 ml), dried(magnesium sulphate) and the solvent evaporated under vacuum to giveN-(6-methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide(106.5 mg).

NMR; δH [²H₆]—DMSO 10.33, (1H, s), 9.93, (1H, s), 8.36, (1H, s), 8.03,(2H, d), 7.77, (3H, m), 7.68, (1H, dd), 7.63, (1H, d), 7.51, (3H, m),7.34–7.28, (3H, m), 6.99, (1H, s), 4.13, (2H, d), 2.84, (3H, d), 2.22,(3H, s). LCMS MH⁺ 504, retention time 3.15 minutes.

Example 17N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}-3-furamide

To a solution of[3′-(3-furoylamino)-6′-methyl-1,1′-biphen-4-yl]carboxylic acid (75 mg),HATU (89 mg) and HOBT (32 mg) in DMF (2.25 ml) was added DIPEA (0.122ml) and N-(4-aminophenyl)methane sulphonamide (44 mg) and the mixturestirred for 18 hours at room temperature. The reaction was partitionedbetween ethyl acetate and hydrochloric acid (0.5M, 20 ml), the organicphase washed with hydrochloric acid (0.5M, 20 ml), saturated sodiumhydrogen carbonate solution (2×20 ml) and water (2×20 ml), dried(magnesium sulphate) and the solvent evaporated under vacuum to giveN-{6-methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}-3-furamide(114.3 mg).

NMR; δH [²H₆]—DMSO 10.31, (1H, s), 9.93, (1H, s), 9.60, (1H, s), 8.35,(1H, s), 8.02, (2H, d0, 7.78–7.74, (3H, m), 7.67, (1H, dd), 7.63, (1H,d), 7.51, (2H, d), 7.29, (1H, d), 7.20, (2H, d), 6.98, (1H, d), 2.95,(3H, s), 2.22, (3H, s). LCMS MH⁺ 490, retention time 3.17 minutes.

Abbreviations DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMEDimethoxyethane DMF Dimethylformamide DMSO Dimethylsulphoxide EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HBTUO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateHOBT 1-Hydroxybenzotriazole hydrate PyBOPBenzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate SPESolid phase extraction THF Tetrahydrofuran

The activity of the compounds of the invention as p38 inhibitors may bedemonstrated in the following assays:

p38 Kinase Assay

The peptide substrate used in the p38 assay wasbiotin-IPTSPITTTYFFFRRR-amide. The p38 and MEK6 proteins were purifiedto homogeneity from E. coli expression systems. The fusion proteins weretagged at the N-terminus with Gluthathione-S-Transferase (GST). Themaximum activation was achieved by incubating 20 uL of a reactionmixture of 30 nM MEK6 protein and 120 nM p38 protein in the presence of1.5 uM peptide and 10 mM Mg(CH₃CO₂)₂ in 100 mM HEPES, pH 7.5, added to15 uL of a mixture of 1.5 uM ATP with 0.08 uCi [g-³³P]ATP, with orwithout 15 uL of inhibitor in 6% DMSO. The controls were reactions inthe presence (negative controls) or absence (positive controls) of 50 mMEDTA. Reactions were allowed to proceed for 60 min at room temperatureand quenched with addition of 50 uL of 250 mM EDTA and mixed with 150 uLof Streptavidin SPA beads (Amersham) to 0.5 mg/reaction. The DynatechMicrofluor white U-bottom plates were sealed and the beads were allowedto settle overnight. The plates were counted in a Packard TopCount for60 seconds. IC₅₀ values were obtained by fitting raw data to %I=100^(*)(1−(I−C2)/(C1−C2)), where I was CPM of background, C1 waspositive control, and C2 was negative control.

α P38 Fluorescence Polarisation Method

αP38 was prepared in house. SB4777790-R Ligand was diluted in HEPEScontaining MgCl₂, CHAPS, DTT and DMSO. This was added to blank wells ofa Black NUNC 384 well plate. αP38 was added to this ligand mixture thenadded to the remainder of the 384 well plate containing controls andcompounds. The plates were read on an LJL Analyst and FluorescenceAnisotropy used to calculate the compound inhibition.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureof combination of features described herein. They may take the form ofproduct, composition, process or use claims and may include, by way ofexample and without limitation, one or more of the following claims:

1. A compound of formula (I):

wherein R¹ is a phenyl group which may be optionally substituted; R² isselected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl; R³ isthe group —NH—CO—R⁴; R⁴ is selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl, trifluromethyl, —(CH₂)_(r)phenyloptionally substituted by R⁵ and/or R⁶, —(CH₂)_(r)heteroaryl optionallysubstituted by R⁵ and/or R⁶, —(CH₂)_(r)heterocyclyl optionallysubstituted by R⁵ and/or R⁶ and —(CH₂)_(r)fused bicyclyl optionallysubstituted by R⁵ and/or R⁶; R⁵ is selected from C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(q)—C₃₋₇cycloalkyl, —CONR⁷R⁸, —NHCOR⁸, —SO₂NHR⁷, —NHSO₂R⁸,halogen, —(CH₂)_(s)NR⁹R¹⁰, oxy, trifluoromethyl, phenyl optionallysubstituted by one or more R⁶ groups and heteroaryl wherein theheteroaryl may be optionally substituted by one or more R⁶ groups; R⁶ isselected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluromethyl and—NR⁹R¹⁰; or R⁵ and R⁶, together with the carbon atoms to which they arebound, form a five- or six-membered saturated or unsaturated ring togive a fused bicyclic ring system, wherein the ring that is formed by R⁵and R⁶ may optionally contain one or two heteroatoms selected fromoxygen, nitrogen and sulfur; R⁷ is selected from hydrogen, C₁₋₆alkyl andphenyl wherein the phenyl group may be optionally substituted by one ormore R⁶ groups; R⁸ is selected from hydrogen and C₁₋₆alkyl; or R⁷ andR⁸, together with the nitrogen atom to which they are bound, form afive- to six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R^(x), whereinthe ring may be substituted by up to two C₁₋₆alkyl groups; R^(x) isselected from hydrogen and methyl; R⁹ is selected from hydrogen,C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyl optionally substituted byC₁₋₆alkyl; R¹⁰ is selected from hydrogen and C₁₋₆alkyl; or R⁹ and R¹⁰,together with the nitrogen atom to which they are bound, form a three-to seven-membered heterocyclic ring optionally containing one additionalheteroatom selected from oxygen, sulfur and N—R^(x), wherein the ringmay contain up to one double bond and the ring may be substituted by oneor more R¹¹ groups; R¹¹ is selected from C₁₋₆alkyl, oxy, —CH₂OC₁₋₆alkyl,trichloromethyl and —N(C₁₋₆alkyl)₂; U is selected from methyl andhalogen; W is selected from methyl and chloro; X and Y are each selectedindependently from hydrogen, methyl and halogen; m is selected from 0,1, 2, 3 and 4, and may be optionally substituted with up to two groupsselected independently from C₁₋₆alkyl; n is selected from 0, 1 and 2; qis selected from 0, 1 and 2; r is selected from 0 and 1; s is selectedfrom 1, 1, 2 and 3; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound according to claim 1 wherein R¹ is substituted byone or two substituents selected from halogen, C₁₋₄alkyl,trifluoromethyl, C₁₋₄alkoxy, benzyloxy, hydroxy, cyano, —CH₂CH₂OH,—(CH₂)_(p)—NHCH₃, —(CH₂)_(p)—N(CH₃)₂, —(CH₂)_(p)CONR⁵R⁶,—(CH₂)_(p)CO₂R⁵, —(CH₂)_(p)NR⁵COR⁶, —(CH₂)_(p)OCOR⁵, —(CH₂)_(p)OCONR⁵R⁶,—(CH₂)_(p)NR⁵COOR⁶, —(CH₂)_(p)COR⁵, —(CH₂)_(p)SO₂NR⁵R⁶,—(CH₂)_(p)NR⁵SO₂R⁶, —SO₂R⁵, —(CH₂)_(p)NR⁵R⁶, —(CH₂)_(p)NR⁵CONR⁵R⁶ and—(CH₂)_(p)CONR⁵SO₂R⁶; wherein p is selected from 0, 1 and 2; and R⁵ andR⁶ are independently selected from hydrogen, C₁₋₄alkyl and phenyl.
 3. Acompound according to claim 1 wherein group R¹ is substituted by one ortwo substituents selected from C₁₋₄alkoxy, hydroxy, —(CH₂)_(p)NR¹⁰SO₂R¹¹and —(CH₂)_(p)NR¹⁰R¹¹; and wherein p is selected from 0, 1 and
 2. 4. Acompound according to claim 1 wherein R² is selected from hydrogen,C₁₋₄alkyl and —CH₂-cyclopropyl
 5. A compound according to claim 4wherein R² is hydrogen.
 6. A compound according to claim 1 wherein m isselected from 0, 1 and
 2. 7. A compound according to according to claim1 wherein R⁴ is selected from —(CH₂)_(r)phenyl optionally substituted byR⁵ and/or R⁶ and —(CH₂)_(r)heteroaryl optionally substituted by R⁵and/or R⁶.
 8. A compound according to claim 7 wherein R⁴ is—(CH₂)_(r)heteroaryl optionally substituted by R⁵ and/or R⁶.
 9. Aprocess for preparing a compound according to claim 1 which comprises:(a) reacting a compound of formula (IX)

wherein R¹, R², U, W, X, Y, m and n are as defined in claim 1, with acompound of formula (X)R⁴CO₂H  (X) wherein R⁴ is as defined in claim 1, under amide formingconditions, optionally converting the acid compound (X) to an activatedform of the acid before reaction with the amine compound (IX); or (b)reacting a compound of formula (XI)

wherein R³, U, W, X, Y and n are defined in claim 1, with a compound offormula (XII)R¹(CH₂)_(m)NR₂H  (XII) wherein R¹, R² and m are as defined in claim 1,under amide forming conditions.
 10. A pharmaceutical compositioncomprising a compound according to any claim 1 or a pharmaceuticallyacceptable salt or solvate thereof, in admixture with one of morepharmaceutically acceptable carriers, diluents or excipients.
 11. Amethod for treating a condition or disease state mediated by p38 kinaseactivity or mediated by cytokines produced by the activity of p38 kinasecomprising administrating to a patient in need thereof a compoundaccording to claim 1 or a pharmaceutically acceptable salt or solvatethereof, and wherein the disease or condition mediated by p38 kinaseactivity or by cytokines produced by the activity of p38 kinase areselected from rheumatoid arthritis, or psoriasis.
 12. The compound whichisN-(4′{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide;or a pharmaceutically acceptable salt or solvate thereof.
 13. Thecompound according to claim 8 wherein the heteroaryl in R⁴ is selectedfrom furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, andtriazinyl.
 14. The compound according to claim 13 wherein the heteroarylis pyridyl, thienyl, oxazolyl, or furyl.
 15. The compound according toclaim 13 wherein the pyridyl is substituted by R⁶ and R⁶ is NR⁹R¹⁰. 16.The compound according to claim 7 wherein r is
 0. 17. The compoundaccording to claim 16 wherein n is
 0. 18. The compound according toclaim 17 wherein X and Y are hydrogen.
 19. The compound according toclaim 18 wherein W is methyl, R² is hydrogen, R¹ is substituted by oneor two substituents selected from C₁₋₄alkoxy, hydroxy,—(CH₂)_(p)NR¹⁰SO₂R¹¹ and —(CH₂)_(p)NR¹⁰R¹¹; and wherein p is selectedfrom 0, 1 and
 2. 20. A compound according to claim 1 which is:N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide;N-{4′-[(4-Methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide;N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;N-(4′-{[(4-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-caroxamide;N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]-phenyl}amino)-carbonyl]-1,1′-biphenyl-3-yl}isoxazole-5-caroxamide;N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)-amino]carbonyl}-1,1′-biphenyl-3-yl)isoxazole-5-carbonoxamide;N-(4′-{[(3-Methoxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide;N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;N-{4′-[({3-[(Dimethylamino)methyl]benzyl}amino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}thiophene-3-carboxamide;N-(4′-{[(3,5-Dihydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;N-(4′-{[(2-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;N-(4′-{[(3-Hydroxybenzyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide;N-(6-Methyl-4′-{[(4-{[(methylsulfonyl)amino]methyl}phenyl)amino]-carbonyl}-1,1′-biphenyl-3-yl)-3-furamide;N-{6-Methyl-4′-[({4-[(methylsulfonyl)amino]phenyl}amino)carbonyl]-1,1′-biphenyl-3-yl}-3-furamide;or a pharmaceutically acceptable salt of solvate thereof.
 21. Apharmaceutical composition comprising a compound according to claim 20or a pharmaceutically acceptable salt or solvate thereof, in admixturewith one or more pharmaceutically acceptable carriers, diluents orexcipients.